654423 research-article2016
TAN0010.1177/1756285616654423Therapeutic Advances in Neurological DisordersJ Zelano
Therapeutic Advances in Neurological Disorders
Poststroke epilepsy: update and future directions
Review
Ther Adv Neurol Disord 2016, Vol. 9(5) 424–435 DOI: 10.1177/ 1756285616654423 © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Johan Zelano
Abstract: Stroke is among the most common causes of epilepsy after middle age. Patients with poststroke epilepsy (PSE) differ in several respects from patients with other forms of structural–metabolic epilepsy; not least in age, age-related sensitivity to side effects of antiepileptic drugs (AEDs), and specific drug–drug interaction issues related to secondarystroke prophylaxis. Encouragingly, there has lately been remarkable activity in the study of PSE. Three developments in PSE research deserve particular focus. First, large prospective trials have established the incidence and risk factors of PSE in the setting of modern stroke care. Stroke severity, cortical location, young age, and haemorrhage remain the most important risk factors. Second, although more studies are needed, epidemiological data indicate that the risk of PSE may be influenced, for instance, by statin treatment. Third, studies are emerging regarding the treatment and prognosis of PSE. Levetiracetam and lamotrigine may be well tolerated treatment options and seizure freedom is achieved in at least a similar proportion of patients as in other epilepsies. Furthermore, new animal models such as photothrombotic stroke gives hope of a more clear understanding of PSE epileptogenesis in the near future. In summary, PSE shows indications of maturing into an independent epilepsy research field. This review summarizes recent advances in our understanding of PSE and provides an update on management issues such as diagnosis, AED selection, and prognosis. Finally, future research challenges in the field are outlined.
Keywords: antiepileptic drugs, seizures, stroke
Introduction Cerebrovascular illness is a major cause of epilepsy after middle age [Forsgren et al. 2005; Syvertsen et al. 2015]. Over the last decade or so, there have been remarkable improvements in the management of stroke, with advances in emergency revascularisation being paralleled by raised ambitions in secondary prophylaxis, rehabilitation, and management of nonmotor sequelae such as fatigue. Poststroke epilepsy (PSE) thereby occurs in an optimistic medical context, but advances in management of poststroke seizures have not quite matched those seen in other stroke treatment domains. In fact, guidance was until recently scarce for neurologists pondering relatively fundamental management issues, such as when to treat whom with what. Fortunately, there seems to be a growing research interest in PSE. This is perhaps part of a general trend in the epilepsy field of increased focus on aetiology.
Traditionally, patients with structural–metabolic epilepsy of widely different origins, from developmental tumours to stroke, were studied under the umbrella term of ‘partial epilepsy’. Although pathways of epileptogenesis may converge, it is clear that structural–metabolic epilepsies of different aetiologies occur in different contexts, medically and demographically, and that management considerations differ in a 30-year old with a low-grade glioma from a 60-year old with hemiparesis and atrial fibrillation.
Correspondence to: Johan Zelano, MD, PhD Department of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, SE41345 Gothenburg, Sweden [email protected]
For clinicians and patients, the focus on aetiology is therefore good news. Better stratification of patients in studies according to underlying aetiology is likely to result in more relevant knowledge and improved management. This review aims to summarize some of the recent advances in PSE research and address some important questions clinicians are likely to face, such as risk factors for
424 http://tan.sagepub.com
J Zelano
Figure 1. Risk-stratification flow chart and treatment algorithm for seizures (that are not considered acute or symptomatic for other reasons) after ischaemic stroke, intracerebral haemorrhage or subarachnoid haemorrhage.
Most risk estimates are from selected observational studies often influenced by AED treatment, varying time limits for early and late seizures, and varying definitions of epilepsy. AED, antiepileptic drugs; ICH, intracerebral haemorrhage; IS, ischaemic stroke; SE, status epilepticus; HT, haemorrhagic transformation; PSE, poststroke epilepsy; SAH, subarachnoid haemorrhage; sz, seizure.
PSE after stroke, the incidence of PSE in the setting of modern stroke care, and an update on current management of PSE. Not all advances have been based on new scientific data. Also covered are policy documents from the International League Against Epilepsy (ILAE) on the definition of acute symptomatic seizures and the definition of epilepsy [Beghi et al. 2010; Fisher et al. 2014], which have spread expert practice and brought valuable structure to the management of PSE.
mainly focused on models of epilepsy after trauma, electric kindling, chemoconvulsant-induced status epilepticus (SE), or cortical injections of irritants such as tetanustoxin or ferrous chloride. Relatively recently, photothrombotic stroke has been established as a model for PSE in rodents [Kelly et al. 2001; Pitkanen et al. 2007], so whether PSE differs from other forms of acquired epilepsy in the most basic mechanisms of epileptogenesis will most likely be elucidated in the near future.
Epileptogenesis, early and late seizures PSE shares features with other forms of structural– metabolic epilepsy. As in, for instance, post-traumatic epilepsy, there is often a latent phase after the insult during which the brain is thought to undergo epileptogenesis and acquire a predisposition for seizures. Among proposed epileptogenic mechanisms are inflammation and remodelling of synaptic networks, perhaps influenced by genetic susceptibility [Silverman et al. 2002; Pitkanen et al. 2015]. Historically, PSE has been difficult to model in rodents, and animal researchers have therefore
The concepts of latency and epileptogenesis form an important basis for clinical understanding of the concept of early versus late seizures. Early seizures occur immediately after a stroke, and are thought to be consequences of local metabolic disturbances that have not necessarily altered neuronal networks, but have made them epileptic in nature. Late seizures occur when epileptogenesis is postulated to have occurred and the brain has acquired a predisposition for seizures [Silverman et al. 2002]. As expected from this model, early and late seizures carry different risks of seizure recurrence (Figure 1). However, the
http://tan.sagepub.com 425
Therapeutic Advances in Neurological Disorders 9(5) Table 1. Summary of selected studies on incidence of poststroke epilepsy published in the last 20 years. Study
n
Study type
Percentage IS/ICH/SAH
Follow up (mean or total)
Outcome measure
Cumulative risk
So et al. [1996] Burn et al. [1997]
535 675
Retrospective Retrospective
100/0/0 81/10/5
5.5 yrs >2 yrs
PSE: 2 sz All seizures > 24 h
Paolucci et al. [1997] Bladin et al. [2000] Lossius [2002]
306
Prospective (rehab inpatient) Prospective
81/19/0
No data
1 LS
86/14/0
9 mths
PSE: 2 sz
92/8/0
12 mths
100/0/0
37.8 mths
PSE: 2 sz after 4 weeks PSE: 2 sz
IS: 8.9% 10-yr risk All: 11.5%, IS 9.7%, ICH 26.1%, SAH 34.3% (5-yr actuarial risk) All: 15% IS: 12% ICH: 27% All: 2.5%, IS: 2.1%, ICH: 2.6% All: 2.5% PSE
93.7/6.3/0
7 yrs
64/36/0
8 mths
PSE: 2 sz and need of AED PSE: 2 sz
Lamy et al. [2003] Kammersgaard and Olsen [2005] Okuda et al. [2012] Arntz et al. [2013b] Graham et al. [2013]
1897 482 581 1195 448
Prospective (age > 60) Prospective (age 18–55) Prospective
93 incl TIA/7/0
9.1yrs
PSE: 2 sz
3310
Retrospective (rehab inpatient) Prospective (age 18–50) Prospective
73.4/13.8/5.7
3.8 yrs
PSE: 2 sz
Jungehulsing et al. [2013] Qian et al. [2014]
1020
Prospective
87/8.7/3.8*
2 yrs
LS > 1 week
935
Prospective
0/100/0
1–16 yrs
Guo et al. [2015] Bryndziar et al. [2015] Serafini et al. [2015] Huttunen et al. [2015]
1832 489
Prospective Retrospective
100/0/0 100/0/0
2.5 yrs 6.5 yrs
PSE: dx in records PSE: 2 sz LS > 2 week
782
Prospective
79.28/14.83/3.2
2 yrs
PSE: 2 sz
876
Retrospective
0/0/100
76 mths
PSE: 1 LS > 1 week
697
IS: 2.3% 3-yr risk All: 3.2% All: 1.3% All: 7%, IS: 8%, TIA: 4%, ICH 23% All: 12.4%, IS: 4.4– 28.7%, ICH: 18.2%, SAH: 21.7% estimated 10-yr risk All: 8.2% 2-yr risk 7% IS: 5% IS: 4.4% LS All: 2.22%, IS 1.97%, ICH: 4.35% SAH: 12% 5-year risk of LS and AED
*Aetiology data only provided for 725 survivors. IS, ischaemic stroke; ICH, intracerebral haemorrhage; SAH, subarachnoid haemorrhage; PSE, poststroke epilepsy; AED, antiepileptic drug; LS, late seizures; sz, seizures; dx, diagnosis.
concept of a latent phase and epileptogenesis reflects our current understanding of epilepsy and may be oversimplified [Loscher et al. 2015]. Some patients with early seizures will develop PSE, and future research, for instance, on biomarkers, may improve our understanding of these cases and aid in their early identification. Epidemiology The reported long-term cumulative risk of PSE after a cerebrovascular event varies between 2% and 15% (Table 1). The variations reflect differences in study cohorts regarding stroke aetiology
or severity and in study methodology such as follow-up time, outcome measures, whether patients remained in the study after subsequent strokes, definitions of late and thus unprovoked seizures, and whether survival was corrected for. Interpretation of observational studies requiring two unprovoked seizures for diagnosis of epilepsy are also complicated by the fact that many patients most likely started AED treatment after the first late seizure. Both early and late seizures are more common after haemorrhage than after infarctions, with the exception of total anterior circulation infarctions,
426 http://tan.sagepub.com
J Zelano Table 2. Independent predictors of poststroke epilepsy in selected studies. Study
Predictors in all patients (mixed aetiology)
Paolucci et al. [1997]
Putaminal haemorrhage Lobar haemorrhage Severity of stroke Young age (
TAN0010.1177/1756285616654423Therapeutic Advances in Neurological DisordersJ Zelano
Therapeutic Advances in Neurological Disorders
Poststroke epilepsy: update and future directions
Review
Ther Adv Neurol Disord 2016, Vol. 9(5) 424–435 DOI: 10.1177/ 1756285616654423 © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Johan Zelano
Abstract: Stroke is among the most common causes of epilepsy after middle age. Patients with poststroke epilepsy (PSE) differ in several respects from patients with other forms of structural–metabolic epilepsy; not least in age, age-related sensitivity to side effects of antiepileptic drugs (AEDs), and specific drug–drug interaction issues related to secondarystroke prophylaxis. Encouragingly, there has lately been remarkable activity in the study of PSE. Three developments in PSE research deserve particular focus. First, large prospective trials have established the incidence and risk factors of PSE in the setting of modern stroke care. Stroke severity, cortical location, young age, and haemorrhage remain the most important risk factors. Second, although more studies are needed, epidemiological data indicate that the risk of PSE may be influenced, for instance, by statin treatment. Third, studies are emerging regarding the treatment and prognosis of PSE. Levetiracetam and lamotrigine may be well tolerated treatment options and seizure freedom is achieved in at least a similar proportion of patients as in other epilepsies. Furthermore, new animal models such as photothrombotic stroke gives hope of a more clear understanding of PSE epileptogenesis in the near future. In summary, PSE shows indications of maturing into an independent epilepsy research field. This review summarizes recent advances in our understanding of PSE and provides an update on management issues such as diagnosis, AED selection, and prognosis. Finally, future research challenges in the field are outlined.
Keywords: antiepileptic drugs, seizures, stroke
Introduction Cerebrovascular illness is a major cause of epilepsy after middle age [Forsgren et al. 2005; Syvertsen et al. 2015]. Over the last decade or so, there have been remarkable improvements in the management of stroke, with advances in emergency revascularisation being paralleled by raised ambitions in secondary prophylaxis, rehabilitation, and management of nonmotor sequelae such as fatigue. Poststroke epilepsy (PSE) thereby occurs in an optimistic medical context, but advances in management of poststroke seizures have not quite matched those seen in other stroke treatment domains. In fact, guidance was until recently scarce for neurologists pondering relatively fundamental management issues, such as when to treat whom with what. Fortunately, there seems to be a growing research interest in PSE. This is perhaps part of a general trend in the epilepsy field of increased focus on aetiology.
Traditionally, patients with structural–metabolic epilepsy of widely different origins, from developmental tumours to stroke, were studied under the umbrella term of ‘partial epilepsy’. Although pathways of epileptogenesis may converge, it is clear that structural–metabolic epilepsies of different aetiologies occur in different contexts, medically and demographically, and that management considerations differ in a 30-year old with a low-grade glioma from a 60-year old with hemiparesis and atrial fibrillation.
Correspondence to: Johan Zelano, MD, PhD Department of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, SE41345 Gothenburg, Sweden [email protected]
For clinicians and patients, the focus on aetiology is therefore good news. Better stratification of patients in studies according to underlying aetiology is likely to result in more relevant knowledge and improved management. This review aims to summarize some of the recent advances in PSE research and address some important questions clinicians are likely to face, such as risk factors for
424 http://tan.sagepub.com
J Zelano
Figure 1. Risk-stratification flow chart and treatment algorithm for seizures (that are not considered acute or symptomatic for other reasons) after ischaemic stroke, intracerebral haemorrhage or subarachnoid haemorrhage.
Most risk estimates are from selected observational studies often influenced by AED treatment, varying time limits for early and late seizures, and varying definitions of epilepsy. AED, antiepileptic drugs; ICH, intracerebral haemorrhage; IS, ischaemic stroke; SE, status epilepticus; HT, haemorrhagic transformation; PSE, poststroke epilepsy; SAH, subarachnoid haemorrhage; sz, seizure.
PSE after stroke, the incidence of PSE in the setting of modern stroke care, and an update on current management of PSE. Not all advances have been based on new scientific data. Also covered are policy documents from the International League Against Epilepsy (ILAE) on the definition of acute symptomatic seizures and the definition of epilepsy [Beghi et al. 2010; Fisher et al. 2014], which have spread expert practice and brought valuable structure to the management of PSE.
mainly focused on models of epilepsy after trauma, electric kindling, chemoconvulsant-induced status epilepticus (SE), or cortical injections of irritants such as tetanustoxin or ferrous chloride. Relatively recently, photothrombotic stroke has been established as a model for PSE in rodents [Kelly et al. 2001; Pitkanen et al. 2007], so whether PSE differs from other forms of acquired epilepsy in the most basic mechanisms of epileptogenesis will most likely be elucidated in the near future.
Epileptogenesis, early and late seizures PSE shares features with other forms of structural– metabolic epilepsy. As in, for instance, post-traumatic epilepsy, there is often a latent phase after the insult during which the brain is thought to undergo epileptogenesis and acquire a predisposition for seizures. Among proposed epileptogenic mechanisms are inflammation and remodelling of synaptic networks, perhaps influenced by genetic susceptibility [Silverman et al. 2002; Pitkanen et al. 2015]. Historically, PSE has been difficult to model in rodents, and animal researchers have therefore
The concepts of latency and epileptogenesis form an important basis for clinical understanding of the concept of early versus late seizures. Early seizures occur immediately after a stroke, and are thought to be consequences of local metabolic disturbances that have not necessarily altered neuronal networks, but have made them epileptic in nature. Late seizures occur when epileptogenesis is postulated to have occurred and the brain has acquired a predisposition for seizures [Silverman et al. 2002]. As expected from this model, early and late seizures carry different risks of seizure recurrence (Figure 1). However, the
http://tan.sagepub.com 425
Therapeutic Advances in Neurological Disorders 9(5) Table 1. Summary of selected studies on incidence of poststroke epilepsy published in the last 20 years. Study
n
Study type
Percentage IS/ICH/SAH
Follow up (mean or total)
Outcome measure
Cumulative risk
So et al. [1996] Burn et al. [1997]
535 675
Retrospective Retrospective
100/0/0 81/10/5
5.5 yrs >2 yrs
PSE: 2 sz All seizures > 24 h
Paolucci et al. [1997] Bladin et al. [2000] Lossius [2002]
306
Prospective (rehab inpatient) Prospective
81/19/0
No data
1 LS
86/14/0
9 mths
PSE: 2 sz
92/8/0
12 mths
100/0/0
37.8 mths
PSE: 2 sz after 4 weeks PSE: 2 sz
IS: 8.9% 10-yr risk All: 11.5%, IS 9.7%, ICH 26.1%, SAH 34.3% (5-yr actuarial risk) All: 15% IS: 12% ICH: 27% All: 2.5%, IS: 2.1%, ICH: 2.6% All: 2.5% PSE
93.7/6.3/0
7 yrs
64/36/0
8 mths
PSE: 2 sz and need of AED PSE: 2 sz
Lamy et al. [2003] Kammersgaard and Olsen [2005] Okuda et al. [2012] Arntz et al. [2013b] Graham et al. [2013]
1897 482 581 1195 448
Prospective (age > 60) Prospective (age 18–55) Prospective
93 incl TIA/7/0
9.1yrs
PSE: 2 sz
3310
Retrospective (rehab inpatient) Prospective (age 18–50) Prospective
73.4/13.8/5.7
3.8 yrs
PSE: 2 sz
Jungehulsing et al. [2013] Qian et al. [2014]
1020
Prospective
87/8.7/3.8*
2 yrs
LS > 1 week
935
Prospective
0/100/0
1–16 yrs
Guo et al. [2015] Bryndziar et al. [2015] Serafini et al. [2015] Huttunen et al. [2015]
1832 489
Prospective Retrospective
100/0/0 100/0/0
2.5 yrs 6.5 yrs
PSE: dx in records PSE: 2 sz LS > 2 week
782
Prospective
79.28/14.83/3.2
2 yrs
PSE: 2 sz
876
Retrospective
0/0/100
76 mths
PSE: 1 LS > 1 week
697
IS: 2.3% 3-yr risk All: 3.2% All: 1.3% All: 7%, IS: 8%, TIA: 4%, ICH 23% All: 12.4%, IS: 4.4– 28.7%, ICH: 18.2%, SAH: 21.7% estimated 10-yr risk All: 8.2% 2-yr risk 7% IS: 5% IS: 4.4% LS All: 2.22%, IS 1.97%, ICH: 4.35% SAH: 12% 5-year risk of LS and AED
*Aetiology data only provided for 725 survivors. IS, ischaemic stroke; ICH, intracerebral haemorrhage; SAH, subarachnoid haemorrhage; PSE, poststroke epilepsy; AED, antiepileptic drug; LS, late seizures; sz, seizures; dx, diagnosis.
concept of a latent phase and epileptogenesis reflects our current understanding of epilepsy and may be oversimplified [Loscher et al. 2015]. Some patients with early seizures will develop PSE, and future research, for instance, on biomarkers, may improve our understanding of these cases and aid in their early identification. Epidemiology The reported long-term cumulative risk of PSE after a cerebrovascular event varies between 2% and 15% (Table 1). The variations reflect differences in study cohorts regarding stroke aetiology
or severity and in study methodology such as follow-up time, outcome measures, whether patients remained in the study after subsequent strokes, definitions of late and thus unprovoked seizures, and whether survival was corrected for. Interpretation of observational studies requiring two unprovoked seizures for diagnosis of epilepsy are also complicated by the fact that many patients most likely started AED treatment after the first late seizure. Both early and late seizures are more common after haemorrhage than after infarctions, with the exception of total anterior circulation infarctions,
426 http://tan.sagepub.com
J Zelano Table 2. Independent predictors of poststroke epilepsy in selected studies. Study
Predictors in all patients (mixed aetiology)
Paolucci et al. [1997]
Putaminal haemorrhage Lobar haemorrhage Severity of stroke Young age (
